Use of n-acetyl-d-glucosamine in the manufacture of pharmaceutical useful for treating motion sickness

ABSTRACT

The present invention has disclosed a use of N-acetyl-D-glucosamine in the manufacture of a medicament for preventing and treating motion sickness, the preparation in which N-acetyl-D-glucosamine is taken as a main active component is able to be used for preventing and treating motion sickness with an effective rate up to more than 90%.

TECHNICAL FIELD

[0001] The present invention relates to the use of N-acetyl-D-glucosamine in the manufacture of a medicament for preventing and treating the motion sickness.

BACKGROUND ART

[0002] Motion sickness is a general denomination of carsickness, seasickness, airsickness and a disease caused by swing, bumping, rotation, accelerated moving and other various factors. The disease often appears several minutes or hours after riding, navigating, flying and other movements. The patient firstly feels uncomfortable at upper stomach, then nauseating, look pale, being in cold sweat; after that, the dizziness, mental depress, secreted sputum increase and vomit will occur; and there will be blood-pressure decreasing, breath turning up and down, nystagmus. Serious vomit may cause deprivation of body fluids and the disorder of electrolyte. Generally, the symptom will disappear or lightened several ten minutes or several hours after stopping the motion or decelerating the velocity, there is also a situation that the patient can not be recovered even several days latter, companied by dispirited, limb asthenia. When the motions or accelerations are repeated, the symptoms may be appeared again.

[0003] The disease is mainly related to the function of vestibule. The cysto- ciliary cell of oval vesicle and sphere vesicle of internal ear labyrinth in the vestibule can mainly feel the linear motion toward up and down, right and left, the ampullary crest ciliary cell of three semicircular canal mainly feel the rotation motion. There are many static cilia and one dynamic cilium in each ciliary cell, the cilia are covered with colloidal membrane consisted of glycoprotein, mucopolysaccharide. The colloidal membrane (ampullae cap, statolithic membrane) can be interacted with cilia to form a location sensor. When starting or stopping the rotation or linear motion, the displacement of inner lymph will lead to the displacement of the colloid membrane, so applying stimulation to the cilia, and the excitation caused by ciliary cell is passed into cerebra through vestibular nerve so as to occur location feeling. The ciliary swing of normal person's ciliary cell is in a chaos rhythm, which is very easy to couple and adapt with a random stimulation caused by outside motion. But the ciliary swing of the ciliary cell of a patient suffered from motion sickness is in a quasi-periodicity, so it is difficult to couple with the random stimulation caused by outside motion, leading to a continuous excitation of the ciliary cell, which is transferred from vestibular nerve to vestibular nerval nucleus, then transferred to cerebellum and hypothalamus in proper order, causing a series of clinic symptoms. The stimulation to vestibular may affect the structure of the net, induce the reduce of blood pressure and vomit. Vestibular nerval nucleus may cause nystagmus from the medial longitudinal fiber to eye muscle motor nuclei; after cerebellum and hypothalamus suffered from nerval impulse, the change of the muscular tension all over the body will be occurred. The stimulation to cerebellum may also be another mechanism of this disease.

[0004] At present, there is not an effective way for preventing and treating the motion sickness. The pending solutions mainly use anti-histamine agents and belladonna agents, or using anti-vomiting agent (metoclopramide), sedative (such as phenobarbital). These medicaments have large side effect, bring many inconvenience to trip and living.

CONTENTS OF THE INVENTION

[0005] The object of the present invention is to provide a new method and medicament for preventing and treating the motion sickness disease.

[0006] The applicant of the present invention is surprised to find that N-acetyl-Dglucosamine and pharmaceutical acceptable salts thereof are able to effectively prevent and cure the motion sickness disease. Because N-acetyl-Dglucosamine has no toxicity, and have a unique curative effect, without influence on the trip and living, so that it can be used widely for a long period.

[0007] Therefore, the present invention is related to a method for preventing and treating the motion sickness, including administrating to a patient who is in need of an effective amount of N-acetyl-D glucosamine and pharmaceutical acceptable salts thereof.

[0008] On the other hand, the present invention is related to the use of N-acetyl-D-glucosamine and pharmaceutical acceptable salt thereof in the manufacture of a medicament for preventing and treating motion sickness disease.

[0009] In the research of “bio-waves” theory, the present inventor has set up a bacterial wave growth model. Through researching, it is known that this wave is of its intrinsic regulation mechanism: some chemical substances are able to participate the regulation in the bio-wave process, so as to transform an abnormal periodic slow wave into a normal physiological chaotic quick wave, and this kind of substances are known as promoting wave factors. Through separating, purifying and identifying, it is determined that one of the factors is N-acetyl-D-glucosamine, the promoting wave function of which is shown in lubricating and protecting the cell. Many biochemical and physiological process of human body need the participation of the promoting wave factors, and it would lead to an abnormal state, if this kind of promoting wave factors is lacked in the living body.

[0010] The structure of N-acetyl-D-glucosamine is as follows:

[0011] N-acetyl-D-glucosamine can be purchased in the market or prepared according to known methods. For instance, patent application WO97/31121 has disclosed a method for preparing N-acetyl-D-glucosamine from chitin by enzyme method, Japanese patent application JP63273493 has disclosed a method in which chitin is partially hydrolyzed into N-acetyl-chitose, and then it is treated with enzyme to obtain N-acetyl-D-glucosamine.

[0012] The pharmaceutical acceptable salts of N-acetyl-D-glucosamine that can be mentioned are the salts formed with pharmaceutical acceptable acids, for instance, the salts formed with inorganic acids, such as hydrochloride, hydrobromide, borate, phosphate, sulfate sulfite and hydrophosphate, and the salts formed with organic acids, such as citrate, benzoate, ascorbate, methyl sulfate, naphthalene-2-sulfonate, picrate, fumarate, maleate, malonate, oxalate, succinate, acetate, tartrate, mesylate, tosylate, isethionate, α-ketoglutarate, α-glyceryl phosphate and glucose-1-phosphate.

[0013] N-acetyl-D-glucosamine is a chemical reagent. From the 1990's, it is continually used to treat pericementitis (WO9102530A1), microbiological infection (WO9718790A3), intestinal inflammation (WO9953929A1), cornea disease (JP10287570A2), hypertrophy of the prostate (U.S. Pat. No. 5,116,615) and so on. It is also applied in cosmetology (JP59013708A2), shampoo preparation (JP2011505A2), tissue growth regulation agent (WO/A 8 702244), and etc., but it has not been used in the manufacture of a medicament for preventing and treating motion sickness.

[0014] The applicant of the present invention has found that N-acetyl-D-glucosamine is able to effectively prevent and treat the motion sickness, because its toxicity and side effect are very little, using N-acetyl-D-glucosamine to prevent and treat motion sickness may avoid undesired side effect caused current medicament for preventing and treating the disease; dependent upon the necessity, small dosage for a long term treatment or large dosage for a temporarily short term treatment can be adopted.

[0015] For the purpose of treating the motion sickness disease, N-acetyl-D-glucosamine can be lonely used or used in the form of a pharmaceutical preparation made by combining with pharmaceutical acceptable excipients or/and carriers. This kind of preparation can be in any form for convenient traditional administrations, preferably, the preparations in the form of liquid or solid for oral administration. A conventional method can be used to prepare the medical compositions in the form of suitable pharmaceutical preparation, for instance mixing, granulating, tableting, sugar coating, film coating and so on. The liquid preparations for oral administration may take aseptic water and aseptic saline solution as carriers, and alcoholic drinks like alcohols may also be taken as carriers. In a preferred embodiment, the concentration of N-acetyl-D-glucosamine in alcoholic drink is 0.1˜4% by weight. For the solid preparations such as tablet or capsule, beside of the compound of formula (I), it may also include diluent, such as lactose, glucose, cellulose, starch, lubricant such as silica, talc, magnesium stearate or calcium stearate, and /or polyglycol; binder such as starch, Arabic gum, methyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone; depolymerizing agent such as starch, alginic acid, aliginate, starch sodium glycolate; foaming mixture; colorant; sweetener; lubricant such as lecithin, polyethenoxy ether and so on.

[0016] Preferably, said medicament is administrated to the patients in need there of by oral with a dosage of 1000˜10000 mg of N-acetyl-D-glucosamine daily in the period from 2˜3 days before the trip by car, navigation or flying to the end of the trip, for preventing and treating the motion sickness disease in a short period.

[0017] In the same way, preferably, said medicament is administrated to the patients in need thereof by oral with a dosage of 200˜2000 mg of N-acetyl-D-glucosamine daily, for preventing and treating motion sickness disease in a long period.

[0018] More preferably, the medicament with alcoholic drink as carrier is administrated to the patient in need thereof by oral with a dosage of 200˜1000 mg of N-acetyl-D-glucosamine daily in the period from 2˜3 days before the trip by car, navigation or flying to the end of the trip.

[0019] Though having no intention to be limited to any theory, the applicant thinks that the motion sickness is substantially a disease caused by losing coupling due to oscillation. As a regulating factor of the bio-waves, N-acetyl-D-glucosamine possesses a wide regulating function to the bio-waves. Through the following three aspects, it is able to develop its special effect in preventing and treating the motion sickness: (1) regulating the rhythmical wave of the cilia in the internal ear ciliary cell. The swinging of ciliary cluster in the ciliary cell is in rhythm, and can be regulated. But N-acetyl-D-glucosamine is able to regulate the quasi-periodic wave of the cilia swing of the ciliary cell of the patient to form a chaos wave, so as to make it easy to couple with outside random rhythm and raise adaptive ability of the patient to the outside motion. (2) regulating the viscosity of ampullae cap and statolithic membrane. Ampullae cap and statolithic membrane are both colloidal membranes formed by glycoprotein as a main component, which transfer the motion of the outside world so as to produce an action to the cilia of ciliary cell, N-acetyl-D-glucosamine is a precursor substance of glycoprotein, which can promote the ciliary cell to secrete glycoprotein so as to raise the viscosity of the colloid membrane. Increasing of viscosity will strengthen the coupling between colloid membrane and cilia, favorable to the coupling between the swing of cilia and outside motion. (3) regulating the excitation of vegetative nerve and vestibule nerve. N-acetyl-D-glucosamine is able to regulate the waves of the nerval cell and network thereof, the continuous single wave transferred from ciliary cell to vestibule nerve, cerebellum, hypothalami and vegetative nerve is regulated into a shape-separating chaos wave, after subjecting to disturbance, the movement of vegetative nerve and vagus nerve is also tend to an absorbed point so as to relieve or remove nauseating, vomiting, look pale, being a cold sweat, dizziness, blood pressure decreasing, nystagmus and so on.

OPTIMAL MODE FOR CARRYING OUT THE INVENTION

[0020] The following experimental examples are used to illustrate the promoting wave function, low toxicity, and the effect for preventing and treating motion sickness disease, of N-acetyl-D-glucosamine (NAG).

[0021] I. Promoting Wave Test of N-acetyl-D-glucosamine

[0022] 1. Experimental Materials and Method:

[0023] 1.1 Samples: Pure Compound of Formula (I)

[0024] 1.2 Experimental Materials:

[0025] Strain: Proteus Mirabilis (which should comply with the following biological reaction characteristics: dynamics (+), urease (+), lactose (−), glucose (+), H₂S (−), phenylalanine deaminase (+).

[0026] Culture medium: modified LB culture medium (the components of the composition are: trytones of 1%, yeast extract of 0.5%, sodium chloride 1%, glucose of 0.1%, TTC of 0.002% and pH=7.2˜7.4).

[0027] 1.3 Experimental Method:

[0028] The Proteus Mirabilis were inoculated at the center of LB plate, incubating at 37° C. for 9 hours, then there were concentric rings emerged, which were extended outward continually with an interval of 3 hours, and this was taken as a control; adding the compound of formula (I) with final concentration of 0.5% onto the LB plate, The Proteus Mirabilis were innoculated by the same method, cultured at 37° C., and the result showed that not only the concentric rings formed with an interval of 3 hours were emerged, comparing with the control, it can be seen that there were also many fine waves on each ring emerged.

[0029] 2. Experimental Results and Evaluation:

[0030] The experiment adopts a bio-wave model which is used to research the promoting wave function of N-acetyl-D-glucosamine. It can be seen from the result that the compound of formula (I) was not only able to cause bacterial cell to reveal a normal bio-wave characteristic, but also cause the wave reveal finer wave mode, and these indicated that N-acetyl-D-glucosamine have promoting function to bio-waves, and the promoting wave function is able to participate the coupling oscillation waving procedure conducted by inner ear ciliary cell and nerve system.

[0031] II. Toxicological Test of the Compound of Formula (I), Including:

[0032] 1. acute toxicity test: including tests of administrating medicine by oral, Intravenous injection and maximum limit amount for administration;

[0033] 2. Ames test;

[0034] 3. micronucleus test of bone marrow cell of mouse;

[0035] 4. abnormal sexual test for the sperm of mouse;

[0036] 5. abnormal aberrance test for the chromosin of mouse's testis;

[0037] 6. chronic lethal test;

[0038] 7. subchronic toxicity ( feed for 90 days) test;

[0039] 8. traditional aberrance-inducing test;

[0040] The results from these tests show that in the acute toxicity test of the compound of formula (I), the dosage more than 2 g/kg is taken, which is 300 times than the injection dosage for human being, but the acute toxicosis reaction had not appeared yet; in the long-period toxicity test, the maximum dosage has reached up to 1 g/kg, and after the treatment and observation for four weeks, there is no toxicosis reaction yet; and in the reproduction test, the mouse was fed with routine dosages from 7 mg/kg for 3 generations, it has been proved that the compound of formula (I) has no influence on the pregnancy, birth, nurse and the growth of baby mice, so it is proved that the compound of formula (I) is a substance without toxicity.

[0041] III. Observation of Curative Efficiency.

[0042] 80 patient suffered from motion sickness were selected and randomly divided into four groups: a group of administrating N-acetyl-D-glucosamine in a long term (800 mg of NAG/person/day), a group of administrating N-acetyl-D-glucosamine in a short term (6000 mg of NAG/person/day), placebo group (6000 mg of glucose/person/day), a group of no administrating medicament. Double blind method was adopted, observing the curative efficiency for traveling 100 kilometers by car (its velocity was 20 kilometers /hour) and traveling 100 kilometers by a small steamboat. Compared with the situation before traveling by car, the following symptoms being relieved or removed will be judged to be effective: dizziness, nauseating and vomiting. The results can be seen from the following table: Number of person Effective Not effective NAG long term group 20 18 2 NAG short term group 20 19 1 Placebo group 20 3 17 No administration 20 2 18

[0043] As shown in the table, the statistic results indicate that the effectivity of preventing and treating the motiom sickness with N-acetyl-D-glucosamine is more than 90%, remarkably differ from the placebo group and the no administration group( p<0.05). 

1. A use of N-acetyl-D-glucosamine and pharmaceutical acceptable salts thereof in the manufacture of a medicament for preventing and treating motion sickness.
 2. The use according to claim 1, wherein said medicament is an oral solution or solid preparation.
 3. The use according to claim 2, wherein said medicament is an alcoholic drink containing 0.1˜4% by weight of N-acetyl-D-glucosamine.
 4. The use according to claim 1, wherein said medicament is administrated to the patients in need thereof by oral with a dosage of 1000˜10000 mg of N-acetyl-D-glucosamine daily from 2˜3 days before the trip by car, navigation or flying to the end of the trip, for preventing and treating the motion sickness in a short period.
 5. The use according to claim 1, wherein said medicament is administrated to the patients in need thereof by oral with a dosage of 200˜2000 mg of N-acetyl-D-glucosamine daily for preventing and treating the motion sickness in a long period.
 6. The use according to claim 3, wherein said medicament is administrated to the patients in need thereof by oral with a dosage of 200˜1000 mg of N-acetyl-D-glucosamin daily from 2˜3 days before the trip by car, navigation or flying to the end of the trip. 